DR Sadik ALGhazzwi Consultant Neurologist MRCP FRCP UK

DR. Sadik AL-Ghazzwi Consultant Neurologist MRCP, FRCP UK Slide 1 of 26

1396: Earliest Recorded Case of MS

HISTORY • • • 1868—Jean-Martin Charcot describes the disease and finds MS plaques (scars) on autopsy. 1878—Louis Ranvier describes the myelin sheath (the primary target of MS in the central nervous system). “Multiple sclerosis is often one of the most difficult problems in clinical medicine. ” (Charcot, 1894) “When more is known of the causes and…pathology of the disease… more rational methods may brighten therapeutic prospect. ” (Gowers, 1898) 1981— 1 st MRI image of MS is published.

What is Multiple Sclerosis (MS)? • CHRONIC Autoimmune demyelination disease of CNS: - brain -optic nerve - and spinal cord • Affects 2. 3 million people in the world Slide 4 of 26

What is the epidemiology of MS? • Geographic distribution Slide 5 of 26

What are the possible risk factors? • • Infections : viral , bacterial, fungal. Age: 15 yr. -45 yr. Gender : female: male 3: 1 Genetic Factors – DR 15 haplotype • Autoimmune diseases • Race • Climate Slide 6 of 26

What are the possible triggers of MS? • Epstein-Barr Virus • Smoking • Vitamin-D deficiency Slide 7 of 26

What is the genetic factor? • The risk of getting MS is approximately: – 1/750 for the general population (0. 1%) – 1/40 for person with a close relative with MS (3%) – 1/4 for an identical twin (25%) • 20% of people with MS have a blood relative with MS The risk is higher in any family in which there are several family members with the disease (aka multiplex families)

What RISKS OF MS? Genetic Predisposition Environmental Trigger Autoimmunity Loss of myelin & nerve fiber Slide 9 of 26

What happens in MS? “Activated” T cells. . . cross the blood-brain barrier… …launch attack on myelin & nerve fibers. . . …to obstruct nerve signals. myelinated nerve fiber Slide 10 of 26

How are myelin autoreactive T-cells activated? • Myelin-reactive T-cells – Myelin basic protein (MBP) • T-cell activation – Autoantigens – Molecular mimicry • Immune cell recruitment – – – CD 8+ cells B cells Granulocytes Monocytes Mast cells Slide 11 of 26

What happens once across the BBB? • Reactivation of CD 4+ cells – Proinflammatory cytokines • Microglial and astrocyte activation – Myelin phagocytosis • Humoral response • B cell co-stimulation • Demyelination – Type II hypersensitivity Slide 12 of 26 https: //michellepetersen 76. files. wordpress. com/2015 /05/discovery-of-a-treatment-to-block-theprogression-of-multiple-sclerosis-

What causes neuronal degeneration? • MS lesions – Active lesions – Inactive, chronic lesions • Demyelination • Immune mechanisms cause: – Oligodendrocyte damage – Injury and loss of axon Slide 13 of 26

Lublin et al, 2014 Slide 14 of 26

Relapsing-Remitting MS • Subacute repeated onset of CNS dysfunction with resolution ( sometimes incomplete , over days to weeks) • Revised Mc. Donald criteria • MRI: Periventricular, brainstem, juxtacortical prominent T 2, often Gad enhancing lesions, T 1 hypointense (black holes)

Secondary Progressive MS • Majority of RRMS many years following onset • Progressive impairment (spastic gait disturbance) between or in absence of attacks

Primary Progressive MS • Presents with progressive myelopathic gait, cerebellar ataxia or cognitive impairment without clear history of any clinical attacks • Clinical progression must be for at least 1 year and accompanied by a combination of brain spinal abnormalities and/or CSF abnormalities consistent with MS • Lack of clinical attacks/ relative paucity of MRI lesions

Clinically Isolated Syndrome (CIS) • A first neurologic event suggestive of demyelination • Individuals with CIS are at high risk for developing clinically definite MS if the neurologic event is accompanied by • multi ple, clinically silent (asymptomatic) lesions on MRI typical of MS 18 Slide 18 of 26

Radiologically Isolated Syndrome (RIS) – No typical symptoms of CNS demyelination – No formally accepted diagnostic criteria – MRI : Typical MS lesions – CSF abnormalities – Clinical MS Attack: – 35% over 5 years – MRI progression: • 59 -83% in 2 years Okuda DT et al, Neurology 2011: 76()8, 686 -692

What are the symptoms of MS? • Early symptoms • Daily effects • Age range • Characteristics of symptoms Slide 20 of 26

Cycle of MS Symptoms: Related and Interdependent Fatigue Depression Sexuality issues Cognitive function Spasticity Constipation Sleep Bladder & Bowel problems Slide 21 of 26

Features Consistent With MS • • Relapses and remissions Age Onset between ages 15 and 50 Optic neuritis Lhermitte's sign Internuclear ophthalmoplegia (INO) Fatigue Uhthoff's phenomenon

How is MS diagnosed? • • • MS is a clinical diagnosis – Medical history – SIGNS And symptoms – Laboratory tests Requires dissemination in time and space: – Space: Evidence of scarring (plaques) in at least two separate areas of the CNS (space) – Time: Evidence that the plaques occurred at different points in time There must be no other explanation Slide 23 of 26

Diagnosis of MS • No single test for diagnosing MS • Usually diagnosed when all other possibilities ruled out • Many tests – Medical history – Nervous system functioning – MRI Mc. Donald criteria – Evoked potential tests, spinal tap Slide 24 of 26

INITIAL SYMPTOMS • ascending numbness starting in the feet; bilateral hand numbness; hemiparesthesia; dysesthesia in one of the above distributions; generalized heat intolerance Slide 25 of 26

• Sensory systems: • -Lhermitte's signdysesthetic painparesthesianumbness-dorsal column signs (i. e. , . severe decrease or loss of vibratory sense and Slide 26 of 26

• Ongoing Symptoms and Signs • Motor system: - • weakness (variable severity mono- and paraparesis, hemiparesis, quadriparesis) • increased spasticity resulting in spastic gait • -pathologic signs (Babinski's, , Hoffmann, , etc. ) -dysarthria Slide 27 of 26

• Cerebellar signs • incoordination (dysdiadochokinesia, problems with heel-to-shin test)-slowing • of rapid repeating movements-cerebellar Slide 28 of 26

Expanded Disability Status Scale Slide 29 of 26

What tests may be used to help confirm the diagnosis? • Magnetic resonance imaging (MRI) • Visual evoked potentials (VEP) • Lumbar puncture Slide 30 of 26

Mc. Donald Diagnostic Criteria MRI-High Specificity & Sensitivity for MS • Typical MS demyelinating lesions meeting at least 3 of the following 4 criteria: – At least 1 Gd lesion or at least 9 T 2 lesions – At least one infratentorial lesion – At least one juxtacortical lesion – At least 3 periventricular lesions Slide 31 of 26

Mc. Donald Diagnostic Criteria MRI-Dissemination in Time • If the first MRI is performed 3 months after the clinical • event, 1 of the 2 below must be found: – > 1 Gd lesion not at site of original attack; or – MRI 3 months later showing a new T 2 or Gd lesion Slide 32 of 26

If the first MRI is performed < 3 months after the clinical event, then a second MRI done 3 months after the attack provides evide nce for 1 of the 2 below must be found: New Gd lesion on the second MRI Later MRI showing new T 2 or Gd lesion 33 Slide 33 of 26

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Case : MRI Brain Slide 35 of 26

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Case 2: MRI Spine Slide 37 of 26

Case 1: Fundoscopy Slide 38 of 26

What role does lumbar puncture play in diagnosis? Ø Spinal fluid can reveal signs of MS q Unique oligoclonal bands in spinal fluid by isoelectric focusing (in 90%-95% of patients with MS) q Elevation of Ig. G index (in 50%-75%) q Mild pleocytosis (in ≈50%) Ø Negative CSF result alone doesn’t rule out MS q But when clinical and radiologic suspicion is low, a normal CSF result reassures patients they probably don’t have MS Ø For RRMS diagnosis q Criteria don’t require confirmation by CSF testing Ø For PPMS diagnosis q Test CSF if MRI features don’t meet criteria for dissemination in space © Copyright Annals of Internal Medicine, 2014 Ann Int Med. 160 (4): ITC 4 -1.

Case : CSF Oligoclonal bands

What are the differential diagnoses? Ø Other demyelinating diseases q Acute disseminated encephalomyelitis q Neuromyelitis optica (Devic disease) q Idiopathic transverse myelitis Ø Systemic inflammatory disease q Systemic lupus erythematosus q The Sjögren syndrome q Sarcoidosis q The Behçet syndrome Ø Metabolic disorders q Adult-onset leukodystrophy q Vitamin B 12 deficiency q Copper deficiency q Zinc toxicity q Vitamin E deficiency © Copyright Annals of Internal Medicine, 2014 Ann Int Med. 160 (4): ITC 4 -1.

Ø Infections q HIV, Lyme disease, syphilis q Human T-lymphotropic virus Ø Vascular disorders q Sporadic and genetic stroke syndromes q CNS vasculitis q Dural arteriovenous fistula Ø Migraine Ø Neoplasia (i. e. , primary CNS neoplasm (glioma or lymphoma) or metastatic disease) Ø Paraneoplastic syndromes © Copyright Annals of Internal Medicine, 2014 Ann Int Med. 160 (4): ITC 4 -1.

An Overview of Treatment Strategies Slide 43 of 26

How is MS treated? • There is no cure for MS • Treatments FOR: – MS attacks or acute relapse. – Immune Modify agents to prevent progression and reduce activity Of the disease. • Treatment of symptoms Slide 44 of 26

HOW SHOULD CLINICIANS CHOOSE THERAPY FOR PATIENTS WHO ARE HAVING AN ACUTE RELAPSE? • Relapse: new or worsening neurologic symptoms lasting ≥ 24 h without clear underlying triggers of pseudo-relapse Ø Standard treatment: high-dose corticosteroids q IV infusion methylprednisolone, 1 g/d for 3 -5 days. Ø OTHER treatment if relapse doesn’t respond to steroids q Plasma exchange q 5 days of IM or SC adrenocorticotrophic hormone. q Pulse-dose IV cyclophosphamide

Disease-Modifying Drugs for RRMS • All reduce attack frequency and severity, reduce lesions on MRI, and probably slow disease progression. • These medications are not designed to: – Cure the disease – Make people feel better – Alleviate symptoms Slide 46 of 26

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How is the disease course treated? • Thirteen disease-modifying therapies are FDA-approved for relapsing forms of MS: – glatiramer acetate (Copaxone®; Glatopa™ - generic equivalent) [inj. ] – interferon beta-1 a (Avonex®, Plegridy™, Rebif®) [inj. ] – interferon beta-1 b (Betaseron® and Extavia®) [inj. ] – dimethyl fumarate (Tecfidera™) [oral] – fingolimod (Gilenya™) [oral]-MELLIOR ORAL – teriflunomide (Aubagio®) [oral] – alemtuzumab (Lemtrada™) [Inj. ] – natalizumab (Tysabri®) [inf] – mitoxantrone (Novantrone®) [inj. ] Slide 48 of 26

Escalation Strategy Disease active Treatment A Mildly effective, mildly toxic Disease suppressed Disease still active Treatment B More effective, more toxic Disease suppressed Disease still active Treatment C Most effective, most toxic

First, second and third line therapies Increasing efficacy Alemtuzumab Natalizumab JC neg Rituximab / ocrelizumab Dimethyl fumarate Autologous stem cell transplantation Mitoxantrone Natalizumab JC+ Fingolimod Daclizumab Laquinimod Glatiramer Teriflunomide Interferon-beta Increasing burden of treatment (worse safety, more difficult administration) Third line Second line First line

High and low risk treatments Increasing efficacy Alemtuzumab Natalizumab JC neg Rituxmab / ocrelizumab Dimethyl fumarate Laquinimod Fingolimod Daclizumab Mitoxantrone Natalizumab JC+ “Dangerous” “Aggressive” Glatiramer Interferon-beta Autologous stem cell transplantation Teriflunomide “Safe” Increasing burden of treatment (worse safety, more difficult administration)

The Changing Landscape of MS Disease Modifying Treatment Of Approved and Emerging Therapies IFNβ-1 a IM qwk Teriflun PO qd Alemtuz IV IFNβ-1 a SC tiw IFNβ-1 b SC qod GA SC qd Mitox IV q 90 d wks Natalizuma b IV q 4 wks BG-12 PO bid Fingolim od 0. 5 mg gd Daclizum ab SC Laquin PO 90 19 92 19 94 19 96 19 98 19 00 20 02 20 04 20 06 20 08 20 10 20 12 20 14 20 Slide 52 of 26

FDA-approved disease modifying agents • Interferon beta – – Interferon beta-1 b (Betaseron®) 250 mcg qod Interferon beta-1 a (Rebif®) 44 mcg SC TIW Interferon beta-1 a (Avonex®) 30 mcg IM weekly. Commn side effects: inj. site reactions, flu like symptoms, abdominal pain, depression, abn. liver function • Glatiramer acetate (Copaxone®) – 20 mgml SC day or 40 mgml 3 timesweek. – Side effects: vasodilatation, rash, sob, chest pain, anexiety. • Mitoxantrone (Novantrone®) – 12 mg/m 2 q 3 mo: lifetime max, 144 mg/m 2 – Side effects: nausea, hair thinning, bladder infection. low wbc, and platletes • Natalizumab (Tysabri®) – 300 mg IV monthly infusion Side effects: UTI, RTI, DIAREA, PML, ENCEPHALITIS Slide 53 of 26

• Continue disease modifying drugus • Parenteral (IV) drugs – Monoclonal antibodies: rituximab/ocrelizumab, alemtuzumab, daclizumab • Oral Drugs – Fingolimod, teriflunomide, Dymethyl fumarate, laquinimod • Symptomatic therapies – Fampridine (4 -AP), nerispirdine Slide 54 of 26

Glatiramare acetate(copaxon) • Glatiramer acetate, the active ingredient of COPAXONE, consists of the acetate salts of synthetic polypeptides • containing four naturally occurring amino acids: Lglutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0. 141, 0. 427, 0. 095, and 0. 338, respectively. The average molecular weight of glatiramer acetate is 5, 000 – 9, 000 daltons. Glatiramer acetate is identified by specific antibodies. Slide 55 of 26

COPAXON • COPAXONE 20 mg per m. L: administer once per day • or • COPAXONE 40 mg per m. L: administer three times per week Slide 56 of 26

Rituximab • Mechanism of action – Chimeric human/murine m. Ab to CD 20 – Depletes circulating B-cells • Dosing – 2 doses given 2 weeks apart IV: 1 g on days 1 and 151 • Side effects – Infusion reactions, infections, hepatitis B reactivation, cases of progressive multifocal leukoencephalopathy in systemic lupus erythematosus/cancer population Approved by FDA for lymphomas, rheumatoid arthritis • • HERMES phase II study for RRMS 1 Randomized, 48 weeks, 104 patients with RRMS – Rituximab 1 g IV vs placebo on days 1 and 15 – 91% decrease in mean total Gd+ lesions § Rituximab 0. 5 ± 2. 0; placebo 5. 5 ± 15 (P <. 0001) – Relapses at 24 weeks § Rituximab 14. 5% vs placebo 34. 3% (P =. 02) • • Neuromyelitis optica/Devic’s open-label study 2 OLYMPUS trial phase II/III in PPMS – ineffective 3 1. Hauser S, et al. N Engl J Med. 2008; 358: 676 -688. 2. Cree BA, et al. Neurology. 2005; 64: 1270 -1272. 3. Hawker KS, et al. Mult Scler. 2008; 14: S 299. Abstr 78. Slide 57 of 26

Alemtuzumab • Mechanism of action – Anti-CD 52 m. Ab to receptor on surface of T- and B-cells § FDA approved for chronic lymphocytic leukemia – Given 12 mgday IV for 5 days (60 mg) followed by 12 mgday for 3 days 12 monthes later. • Alemtuzumab CAMSS 223 Phase II trial 1 – 334 early RRMS patients randomized to alemtuzumab vs interferon beta-1 a § 2 -year follow-up results – Alemtuzumab group: 75% reduction in relapse rate vs interferon beta 1 a – Significant reduction of risk of sustained disability § 3 -year follow-up – Maintained 71% and 74% reduction in risk of sustained disability and relapse rate, respectively, vs interferon beta-1 a § 2 phase III trials (CARE-MS, CARE-MS 2) now enrolling • Serious adverse events – Infusion reactions – Idiopathic thrombocytopenic purpura (3%): total of 6 cases – 1 st case was fatal – Grave’s disease – autoimmune thyroiditis (20%) Slide 58 of 26

Daclizumab • Mechanism of action – Anti-CD 25 m. Ab targeting α chain of IL-2 receptor (IL-2 Rα) – Blocks the IL-2 “proinflammatory, ie, bad” cytokine receptor – Prevents activation of sensitized T-cells • Dosing – IV infusion every 2 weeks (high dose) or every 4 weeks (low dose) Side effects – infections, cutaneous reactions • FDA approved for graft versus host disease/kidney transplant rejection – CHOICE Trial – phase II results 1 § Randomized double-blind controlled trial § Add-on to interferon in 230 patients with RRMS § 3 arms: 2 doses of daclizumab and placebo added to interferon – Results § Decrease in new MRI lesions with higher dose vs interferon alone § No significant difference in relapse rate § 5. 2% with significant infections, none life-threatening – SELECT: phase II trial of daclizumab monotherapy – Ongoing 1. Montalban X, et al. Mult Scler. 2007; 13: S 7 -S 273. Abstr 50. Slide 59 of 26

Teriflunomide( Aubagio) • Mechanism of action – Inhibits pyrimidine (DNA) synthesis in T-cells resulting in destruction of immune cells • Dosing – Once-daily 7 mg or 14 mgday • Side effects: alopecia, diarrhea, flu, liver injury, renal failure • Results of phase II trial 1: 36 weeks in 179 patients – Teriflunomide (high dose and low dose) vs placebo – Significant (>61%) decrease in new MRI lesions in both doses – Decrease in disease progression (in high dose) – Trend towards lower relapse rate in high-dose group . Slide 60 of 26

FINGOLIMOD Sphingosine-1 -Phosphate (S 1 P) Receptor Agonist Slide 61 of 26

Fingolimod: Mechanism of Action Multiple sclerosis S 1 P receptor FTY 720 traps circulating lymphocytes in peripheral lymph nodes T-cell FTY 720 -P LN Prevents T-cell invasion of central nervous system FTY 720 Sphingosine-1 -phosphate (S 1 P) receptor modulator Internalises S 1 P 1, blocks lymphocyte egress from lymph node (LN) while sparing immune surveillance by peripheral memory T-cells Slide 62 of 26

Fingolimod • Treatment with fingolimod 0. 5 mg: – Significant benefits on relapse-related outcomes within first 3 months and on volume loss over 6 months compared with PBO in FREEDOMS and FREEDOMS II studies; concordant results from 2 large phase 3 trials, along with phase 2 data, allow better definition of expectations regarding time lag between initiation and effects of fingolimod treatment Slide 63 of 26

Relapsing inflammatory MS clinical course First line Inadequate response/inj intolerance Injectable therapies Interferon β Parallel switch Glatirame r Inadequate response/oral intolerance First line? Severe relapsing inflammatory MS/JCV negative Oral therapies Consider side effects BG 12 Fingolimod 0, 5 mg day DIMETHYL FUMARATE Terflunomide Inadequate response/JCV negative Natalizumab 300 MG I. V inj. month Slide 64 of 26

Dimethyl Fumarate (TECFIDERA)(sclera) : A New Small Molecule Disease. Modifying Drug for Multiple Sclerosis 120 mg PO BID initially; after 7 days, increase to maintenance dose of 240 mg BID Slide 65 of 26

Dimethyl fumarate (TECFIDERA) is an orally administered fumarate ester FDA approved for first-line monotherapy of multiple sclerosis in 2013. Because it is rapidly and completely hydrolyzed by esterases before reaching the systemic circulation, the pharmacologic activity of dimethyl fumarate is due to its active metabolite, monomethyl fumarate Slide 66 of 26

Although the precise mechanism of action is incompletely characterized, monomethyl fumarate is thought to exert neuroprotective effects in patients with multiple sclerosis by activating the nuclear erythroid 2 -related factor 2 (nuclear factor erythroid-derived 2 -like 2; Nrf 2) transcriptional pathway. Using a model of endogenous neuronal oxidative stress Slide 67 of 26

Proposed Mechanism of Action of Dimethyl Fumarate. Abbreviations used: ARE, antioxidant response element; GCLC, glutamate-cysteine ligase; GSH, glutathione; Gst. A 2, glutathione S-transferase A 2; HO-1, hemeoxygenase-1; Nqo 1, NADPH quinone oxidoreductase 1; MMF, monomethyl fumarate; Nrf 2, nuclear factor erythroid -derived 2 -related factor 2. Comments Slide 68 of 26

What is the prognosis? • One hallmark of MS is its unpredictability. – Approximately 1/3 will have a very mild course – Approximately 1/3 will have a moderate course – Approximately 1/3 will become more disabled • Certain characteristics predict a better outcome: – Female – Onset before age 35 – Sensory symptoms – Monofocal rather than multifocal episodes – Complete recovery following a relapse Slide 69 of 26

Who is on the MS “Treatment Team”? • • Neurologist Urologist Nurse Physiatrist Physical therapist Occupational therapist Speech/language pathologist • Psychiatrist • Psychotherapist • Neuropsychologist • Social worker/Care manager • Pharmacist • Primary care physician Slide 70 of 26

What is the prognosis? • One hallmark of MS is its unpredictability. – Approximately 1/3 will have a very mild course – Approximately 1/3 will have a moderate course – Approximately 1/3 will become more disabled • Certain characteristics predict a better outcome: – Female – Onset before age 35 – Sensory symptoms – Monofocal rather than multifocal episodes – Complete recovery following a relapse

So what do we know about MS? • MS is a chronic, unpredictable disease • The cause is still unknown • MS affects each person differently; symptoms vary widely • MS is not fatal, contagious, directly inherited, or always disabling • Early diagnosis and treatment are important – Significant, irreversible damage can occur early on – Available treatments reduce the number of relapses and may slow progression • Treatment includes: attack management, symptom management, disease modification, rehab, emotional support Slide 72 of 26

• QUESTIONS Slide 73 of 26

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THANK YOU Slide 75 of 26